Hemoglobin composition and concentration are the primary determinants of polymer formation in erythrocytes containing sickle hemoglobin (SS). Polymer formation can be experimentally measured or calculated from a thermodynamic analysis. Polymer formation decreases with increasing oxygen saturation and polymer is present in vivo at high oxygen saturations (greater than 80% or 90%). Calculations of polymer formation which have now been extended to other sickle syndromes, based on the average hematologic profile, can explain to a large degree (about 80%) the variation in hemolytic severity associated with twelve different sickle syndromes. The effects of cell heterogeneity within a sickle syndrome were examined for sickle cell anemia, with and without co-existing alpha-thalassemia, in terms of intracellular hemoglobin composition and hemoglobin concentration. The broad distribution in erythrocyte density, the large proportion of dense cells and the accelerated increase in cell density beyond normal cell aging in sickle cell anemia are reduced with coexisting alphathalassemia. The hemoglobin F production, reflected in the percentage of hemoglobin F containing reticulocytes and the proportion of hemoglobin F per F-cell remains unchanged. Studies of intracellular hemoglobin composition and concentration are being used to evaluate therapeutic strategies. For example, 5-azacytidine and hydroxyurea treatment increase hemoglobin F production while decreasing hemoglobin S production. The effect of these treatments on cell density is being monitored to determine changes in the polymerization potential of the sickle cell. Studies of non-covalent modifiers of gelation are continuing with x-ray crystallographic analysis and energy minimization calculations to determine experimentally and theoretically possible binding sites of peptides which might mimic an intermolecular binding region. These studies will be used to improve the specificity of these potential therapeutic agents.